Design,Synthesis, Configuration Research,and In Vitro Antituberculosis Activities of two Chiral Naphthylamine Substituted Analogs of Bedaquiline

Two chiral naphthylamine‐substituted analogs of Bedaquiline were selected from a series of compounds designed as anti‐tuberculosis drugs based on the structure activity relationship of bedaquiline for synthetic and stereochemical research. The compounds were synthesized from the chiral precursors for the first time, and their absolute configurations were determined by electronic circular dichroism and quantum chemical calculations. Conformational analyses were performed on the compounds to find the stable conformers and get better predicted results. In addition, the in vitro antituberculosis activities of the two compounds were investigated.     

Polypeptidic Micelles Stabilized with Sodium Alginate Enhance the Activity of Encapsulated Bedaquiline

The coating of polypeptidic micelles with sodium alginate is described as a strategy to improve the stability of micelles for drug delivery. Bedaquiline, approved in 2012 for the treatment of multidrug resistant tuberculosis, has been used as an example of hydrophobic drug to study the loading efficiency, the release of the encapsulated drug in different media, and the in vitro antimicrobial activity of the system. Alginate coating prevents the burst release of the drug from micelles upon dilution and leads to a sustained release in all tested media. In view of possible oral administration, the alginate coated micelles show better stability in gastric and intestinal simulated media. Notably, the encapsulated bedaquiline shows increased in vitro activity against Mycobacterium tuberculosis compared to free bedaquiline.     

基于局部最小二乘支持向量机的光谱定量分析

提出了一种基于局部最小二乘支持向量机(LSSVM)的回归方法,以克服待测参数和光谱数据间的非线性。本方法首先通过欧式距离选取局部训练样本子集,然后利用该子集建立LSSVM校正模型。由于每个测试样本建模时要选取不同的训练样本,因此提出相对距离的概念用来改进高斯核函数,使LSSVM的参数对于不同的训练样本具有自调整功能。针对一批汽油样本的实验结果表明,本方法的预测精度优于常见的局部线性建模方法和全局建模方法。     

Local chemometrics for samples and variables: optimizing calibration and standardization processes

The ability of five sample selection methods for local chemometrics and three variable selection algorithms were compared for the development and the transfer of whole soybeans protein and oil near infrared prediction models. Two new methods based on a similarity index considering Euclidian distance among Fourier coefficients were introduced and tested against more common approaches (locally weighted regression, LOCAL). Genetic algorithms were also challenged with the development of models based on particle swarm optimization (PSO). A modification to the original PSO model was introduced. Sample and variable selection methods, as well as their combinations, were tested in the transfer of models in intra‐ and inter‐brand situations using two Foss Infratecs and two Bruins OmegAnalyzerGs. For each brand, a master was designated and its models transferred onto the second unit of its network and the two units of the second brand. Calibration models were proven transferable from brand to brand with similar or better precisions than when all instruments were calibrated on their own calibration sets (relative predictive determinant (RPD) improving from 10.42 to 12.76 and 12.39 in intra‐brand standardization for Infratec network with local and variable selection methods respectively). These methods provided contrasted results depending on the instrument, the parameter, and the variability of interest. Copyright © 2010 John Wiley & Sons, Ltd.     

Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline**

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.     

基于单体烃分析的辛烷值测定方法中模糊聚类技术的应用研究

介绍了一种应用模糊聚类技术构建辛烷值预测模型的新方法。该模型用来由汽油单体烃数据预测汽油辛烷值,通过提取单体烃分析谱图中的140个工艺特征组分以及对辛烷值贡献大的组分为特征值进行模糊聚类。实际应用时,在待测汽油样品共同参与聚类的条件下,用与待测汽油样品为同一类、并有最小欧氏距离(<1.5)的3~10个样本作为构建辛烷值预测模型的样本。这种按新的建模样本选择方式得到预测模型的方法具有更好的辛烷值预测精度、更广的适用范围和更高的数据资源的利用率。     

基于质子转移反应-飞行时间质谱快速鉴别不同产地闽北水仙茶

采用质子转移反应-飞行时间质谱仪(PTR-TOF-MS), 构建了3个产地(武夷山、建阳、建瓯)113个闽北水仙茶样品香气的化学指纹图谱, 对所得的闽北水仙茶香气指纹图谱进行主成分分析(PCA), 获得了不同产地闽北水仙茶样品的质谱信息特征, 然后采用软独立建模分类法(SIMCA)、K最邻近结点算法(KNN)、偏最小二乘判别分析法(PLS-DA)对闽北水仙茶的质谱信息进行了模式识别.结果表明, PTR-TOF-MS结合分类识别模式能有效区分不同产地的闽北水仙茶.PCA 提取了3个主成分, 累计贡献率为84.66%;3个识别模型的校正集判别正确率分别为89.38%、100.00%和100.00%, 预测集的判别正确率分别为83.18%、 96.46%和95.57%.基于此成功建立了不同产地的闽北水仙茶识别模型.本方法无需样品预处理、分析速度快、灵敏度高、对茶叶无损伤, 为茶叶产地溯源提供了新方法.     

Autofluorescence of oral tissue for optical pathology in oral malignancy

Pulsed laser-induced-fluorescence studies of pathologically certified oral tissues are carried out at different excitations and time delays. Among the several excitations used, 325 nm produced noticeably different spectral profile for normal and malignant tissues. Extensive curve analysis was carried out in order to understand changes in biochemical composition of tissue based on spectral profiles. Curve resolution and principal component analysis (PCA) show that the fluorescence intensity changes from normal to malignant tissue samples are not completely explained in terms of simple collagen and NAD(P)H intensity changes. The spectra require at least five components to be fully accounted for. Several discrimination methodologies based on PCA and intensity differences between different emission peaks (resultant peaks of curve analysis) were also evaluated. The results obtained indicate PCA using Mahalanobis distance and spectral residual as discrimination parameters provides best discrimination and can be used for matching unknown samples to standard calibration sets. Intensity ratio of bound NAD(P)H to collagen seems to be more suitable for discrimination between normal and malignant oral tissue, compared to ratio of collagen to total intensity of all the other components together.     

Multi-wavelength HPLC fingerprints from complex substances: An exploratory chemometrics study of the Cassia seed example

Multi-wavelength fingerprints of Cassia seed, a traditional Chinese medicine (TCM), were collected by high-performance liquid chromatography (HPLC) at two wavelengths with the use of diode array detection. The two data sets of chromatograms were combined by the data fusion-based method. This data set of fingerprints was compared separately with the two data sets collected at each of the two wavelengths. It was demonstrated with the use of principal component analysis (PCA), that multi-wavelength fingerprints provided a much improved representation of the differences in the samples. Thereafter, the multi-wavelength fingerprint data set was submitted for classification to a suite of chemometrics methods viz. fuzzy clustering (FC), SIMCA and the rank ordering MCDM PROMETHEE and GAIA. Each method highlighted different properties of the data matrix according to the fingerprints from different types of Cassia seeds. In general, the PROMETHEE and GAIA MCDM methods provided the most comprehensive information for matching and discrimination of the fingerprints, and appeared to be best suited for quality assurance purposes for these and similar types of sample.     

Solid-phase extraction versus matrix solid-phase dispersion: Application to white grapes

The use of matrix solid-phase dispersion (MSPD) was tested to, separately, extract phenolic compounds and organic acids from white grapes. This method was compared with a more conventional analytical method previously developed that combines solid liquid extraction (SL) to simultaneously extract phenolic compounds and organic acids followed by a solid-phase extraction (SPE) to separate the two types of compounds. Although the results were qualitatively similar for both techniques, the levels of extracted compounds were in general quite lower on using MSPD, especially for organic acids. Therefore, SL-SPE method was preferred to analyse white “Vinho Verde” grapes. Twenty samples of 10 different varieties (Alvarinho, Avesso, Asal-Branco, Batoca, Douradinha, Esganoso de Castelo Paiva, Loureiro, Pedernã, Rabigato and Trajadura) from four different locations in Minho (Portugal) were analysed in order to study the effects of variety and origin on the profile of the above mentioned compounds. Principal component analysis (PCA) was applied separately to establish the main sources of variability present in the data sets for phenolic compounds, organic acids and for the global data. PCA of phenolic compounds accounted for the highest variability (77.9%) with two PCs, enabling characterization of the varieties of samples according to their higher content in flavonol derivatives or epicatechin. Additionally, a strong effect of sample origin was observed. Stepwise linear discriminant analysis (SLDA) was used for differentiation of grapes according to the origin and variety, resulting in a correct classification of 100 and 70%, respectively.     

UV photoelectron spectroscopic study of substituent effects in quinoline derivatives

The molecular and electronic structure of eight substituted quinolines has been investigated by HeI/HeII photoelectron spectroscopy, Green's function calculations, and comparison with the spectra of related compounds. The correlation between nitrogen lone pair ionization energies and basicity in 18 substituted quinolines is discussed. The influence of different substituents has been quantified via the scheme that is based on experimental energy shifts. The relationships between nitrogen ionization energies, pK(a) values, and medicinal activity are also discussed.     

Parallel synthesis and antimalarial screening of a 4-aminoquinoline library

Due to growing problems with drug resistance, there is an outstanding need for new, cost-effective drugs for the treatment of malaria. The 4-aminoquinolines have provided a number of useful antimalarials, and Plasmodium falciparum, the causative organism for the most deadly form of human malaria, is generally slow to develop resistance to these drugs. Therefore, diverse screening libraries of quinolines continue to be useful for antimalarial drug discovery. We report herein the development of an efficient method for producing libraries of 4-aminoquinolines variant in the side chain portion of the molecule. The effects of these substitutions were evaluated by screening this library for activity against P. falciparum, revealing four potent compounds active against drug-resistant strains.     

三维全息原子场作用矢量(3D-HoVAIF)用于神经氨酸酶抑制剂的结构表征与设计及定量构效关系(QSAR)研究

对100个神经氨酸酶抑制剂抗禽流感药物结构并与其活性建立定量构效关系模型。采用本实验室提出的三维全息原子场作用矢量(3D-HoVAIF)对100个神经氨酸酶抑制剂进行结构表征,然后采用逐步回归对变量进行筛选后,运用偏最小二乘建立3D-HoVAIF描述子与神经氨酸酶抑制剂活性之间的QSAR模型。结果表明:复相关系数(R),交互校验的复相关系数(Q2)和模型的标准偏差(SD)分别为R2=0.805、Q2=0.657和SD=0.936,模型具有良好的稳定性和预测能力,并对文献中23个药物和设计的32个化合物进行了预测。表明三维全息原子场作用矢量能较好表征该类分子结构信息值得进一步推广应用。     

药物水溶解度的QSAR研究和VolSurf参数

药物的水溶解度与其吸收密切相关。本文利用一种新的计算方法,VolSurf,预测药物的水溶解度并测定有利于药物水溶解度的主要分子特征。被测化合物包括26个结构不同的药物,通过偏最小二乘分析法,对药物水溶解度实验值与分子特征进行相关,得到较好的模型(r2=0.90,q2=0.77)。将化合物分为训练集和预测集进行相关分析,结果表明以18个化合物所建立的训练集模型对其余8个化合物有较好的预测能力,预测的标准偏差(SDEP)为0.59。参数分析表明分子与水相互作用的3个局部能量最小值越小,且它们之间的距离越大,对其水溶解度越有利;亲水性占主导因素的分子有高的水溶解度;分子的疏水性越强,在水中的溶解性越弱;大分子的溶解度较小分子溶解度低。     

Current Progress in the Development of Hepatitis B Virus Capsid Assembly Modulators: Chemical Structure,Mode-of-Action and Efficacy

Hepatitis B virus (HBV) is a major causative agent of human hepatitis. Its viral genome comprises partially double-stranded DNA, which is complexed with viral polymerase within an icosahedral capsid consisting of a dimeric core protein. Here, we describe the effects of capsid assembly modulators (CAMs) on the geometric or kinetic disruption of capsid construction and the virus life cycle. We highlight classical, early-generation CAMs such as heteroaryldihydropyrimidines, phenylpropenamides or sulfamoylbenzamides, and focus on the chemical structure and antiviral efficacy of recently identified non-classical CAMs, which consist of carboxamides, aryl ureas, bithiazoles, hydrazones, benzylpyridazinones, pyrimidines, quinolines, dyes, and antimicrobial compounds. We summarize the therapeutic efficacy of four representative classical compounds with data from clinical phase 1 studies in chronic HBV patients. Most of these compounds are in phase 2 trials, either as monotherapy or in combination with approved nucleos(t)ides drugs or other immunostimulatory molecules. As followers of the early CAMs, the therapeutic efficacy of several non-classical CAMs has been evaluated in humanized mouse models of HBV infection. It is expected that these next-generation HBV CAMs will be promising candidates for a series of extended human clinical trials.